This projects delineates biochemical and pharmacological properties of sigma receptors and ligands. We have discovered a protein which resembles the opioid/sigma receptors and continued to work on its final purification. Our results with heparin being a potent uncompetitive inhibitor at sigma receptors suggest that sigma receptors are related to intracellular calcium mobilization. A separate experiment with dantrolene have indicated that a portion of the calcium efflux from the endoplasmic reticulum in the cells is not under the control of the free intracellular calcium concentration. We are beginning to get ready to use confocal microscope to further examine the role of sigma receptors in the regulation of intracellular calcium mobilization. On the behavioral level, in addition to showing that PRE-084 - a selective sigma ligand discovered at the NIDA IRP - could reverse the learning and memory deficit inherited in senescence accelerated mouse (SAM), we have now obtained evidence that PRE-084 reversed the beta- amyloid(25-35)-induced cognitive deficit in mouse. This property of PRE-084, interestingly, is shared by neurosteroids DHEAS and pregnenolone sulfate which have been shown to be active at sigma receptors. Further, progesterone - a sigma ligand with nanomolar affinity, antagonized the memory-improving properties of all three compounds.